The goal of this proposal is to determine the molecular genetic, biochemical and physiological changes associated with two related life-extending interventions, caloric restriction and the long-lived Indy mutation. Caloric restriction (CR) is the most successful way to increase life span and delay the onset of age-related symptoms in animals. CR slows down the physiological decline and occurrence of age-related pathologies in a number of different experimental organisms. Mutations in the Indy gene in the fruit fly, Drosophila melanogaster, dramatically extend life span without a decrease in metabolic rate, physical activity or fertility. INDY is a dicarboxylate transporter of Krebs cycle intermediates and is primarily found in the plasma membrane of midgut, fat body, and oneocytes, tissues important for intermediary metabolism in the fly. The life extending effect of reducing Indy activity has been proposed to result from changes similar to those associated with CR. We will test whether Indy long-lived mutations have induced a state of CR by comparing the mortality rate, metabolic profile (e.g. lipids, glucose, glycogen, etc.) and genomic transcriptional responses of Indy long-lived flies and calorically restricted flies. In the course of these studies we will focus on determining the physiological and molecular responses to caloric restriction that lead to life span extension in the fly in order to achieve our long-term goal of understanding the molecular genetic mechanisms underlying the process of aging.